Imatinib (N-{5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine) is represented by the following structural formula (I):

Imatinib is known as an inhibitor of tyrosine kinases and is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib is sold by Novartis as Gleevec™ capsules containing Imatinib mesylate equivalent to 100 mg of imatinib free base.
U.S. Pat. No. 5,521,184 and application WO 03/066613 describe several synthetic routes for preparing Imatinib. One synthetic process, described in Scheme 1, comprises reacting 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester with 3-nitro-4-methyl-aniline to obtain N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reduced to obtain N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with cyanamide (NH2CN) in a mixture of concentrated hydrochloric acid solution and n-butanol to produce N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain Imatinib.

Another process, described in Scheme 2, comprises obtaining 2-methyl-5-nitrophenyl-guanidine from 2-amino-4-nitro-toluene by adding nitric acid to a solution of the latter in ethanol followed by addition of cyanamide. The product is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, which is subsequently reduced and reacted with 4-(4-methyl-piperazinomethyl)-benzoyl chloride to obtain Imatinib.

Yet another process, described in Scheme 3, comprises reacting 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester to obtain N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with 4-(3-pyridyl)-2-pyrimidine amine (which is obtained by reacting cyanamide with 3-dimethylamino-1-pyridin-3-yl-propenone) to obtain Imatinib

The common feature of the above processes for preparing Imatinib, according to U.S. Pat. No. 5,521,184 and application WO 03/066613, which are described herein, is the usage of cyanamide as a reagent. However, the usage of cyanamide in the pharmaceutical industry is disadvantageous, because it is a highly toxic, hazardous and corrosive reagent. Contact of cyanamide with water, acids or alkalies may cause violent reaction and mixing of cyanamide with certain chemicals such as diamines can cause an explosion. The recommended exposure limit of cyanamide is 2 mg per cubic meter and therefore “Good Manufacturing Practice” requires the use of industrial respirators to control the exposure as well as adequate ventilation in the production place. Furthermore, the workers dealing with cyanamide should use appropriate personal protecting clothing to prevent skin contact with cyanamide. These safety measures complicate the production procedures and increase the production costs.
Some other experimental procedures, described in U.S. Pat. No. 5,521,184 and application WO 03/066613, are even less applicable to industrial purposes. These include, for example, the reaction between N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidine amine which uses a reagent mixture of rac-BINAP (a phosphine oxide catalyst) and Pd2(dba)3*CHCl3 (Example 10 in patent application WO 03/066613). These catalysts are very expensive and therefore their use is unfit for commercial production.
The last step in Imatinib synthesis, namely the coupling reaction between N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine and 4-(4-methyl-piperazin-1-ylmethyl)-benzoyl chloride is described in application WO 2004/074502, wherein DMF is used instead of pyridine. The inventors of application WO 2004/074502 have stated that using pyridine can be disadvantageous because it is difficult to remove residual traces from the final product.
Therefore, there is a need in the art for a process of preparing Imatinib that is less hazardous and more environmentally friendly.